Issues with Treatment

Over the last decade there has been controversy in the medical community over treatment for borreliosis: one point of view is that it is easy to treat; the other that it needs aggressive treatment with antibiotics and other interventions. Until now, the first point of view has mostly prevailed in the UK medical community.

However, recent research at Northeastern University and Johns Hopkins University has shown that the bacterium which causes Lyme Disease forms dormant ‘persister’ cells, which are known to evade antibiotics. These make Lyme disease as difficult to treat as TB or leprosy. Treatment protocols needs to be modified to address the complexity of borrelia infection.

A recent retrospective study from the Netherlands concluded that "residual symptoms following treatment were found in 28.1% of patients, and risk of residual symptoms was significantly associated with delay from symptom debut to initiation of treatment".

Uncertainties

Many uncertainties exist which are not being acknowledged fully within NHS Scotland at present. The top 10 uncertainties in the diagnosis and treatment of Lyme Disease were agreed by clinicians and patients in a recent UK-based rigorous analysis by the UK Lyme Disease Priority Setting Partnership undertaken by Lyme Disease Action and the James Lind Alliance.

A recent set of reviews commissioned by the Department of Health in England, concluded that "a better understanding of how to deal with the negative impact of uncertainties surrounding Lyme disease diagnosis is needed". There was such a lack of research evidence regarding treatment that they "were unable to produce a review of treatment experiences".

In “Overview of Lyme Disease: A Critique of an Ignored Pandemic,” it is suggested that 20% of the human population is infected and may well explain diseases of unknown origin. "It is history repeating itself but matters are more serious as no one was denying the existence of syphilis a hundred years ago, but many deny the existence of Lyme disease".

Existing Guidelines are Out-of-Date

Guidelines developed by the Infectious Diseases Society of America (IDSA) have been used for treatment in Scotland. These guidelines were developed in 2006, before the recent medical understanding of the complexities of borrelia and persistence. The IDSA guidelines have been removed from the US National Guidelines Clearinghouse because they are considered too out-of-date. IDSA have not produced more recent guidelines.

In September 2016, France became the first country to release a national plan to address tick-borne diseases like Lyme (English translation here). It ranges from ramped-up surveillance of ticks and infections to better treatment protocols and diagnostic tests and specialist treatment centres. An interview with a leading French doctor explains how it evolved.

A French national protocol for diagnosis and care was pre-announced in March 2018 and formally announced in July 2018.

In March 2017, in Canada's Federal Framework on Lyme Disease Act they have stated "the current guidelines in Canada are based on those in the United States and are so restrictive as to severely limit the diagnosis of acute Lyme disease and deny the existence of continuing infection, thus abandoning sick people with a treatable illness". They have committed $4 milion to the framework.

In March 2018, the New York State Senate allocated $1 million towards combatting the ''growing epidemic'. In May they announced a comprehensive package of legislation to combat Lyme and tick-borne diseases including incrased public awareness, prevention measures, testing, review of blood donations, notification of Lyme as a cause of death, development of treatment protocols and extension of insurance cover.

It has taken 7 years following an Early Day Motion at Westminster to get agreement for development of such guidelines in England. Guidelines have now been issued. However, they are narrow in scope, do not fully address persistence, do not include guidelines for co-infections, and some recommendations are based on no evidence whatsoever. Research recommendations include development of a core outcome set for clinical trials; research into incidence, features, management and outcomes; research into seroprevalence of co-infections in the UK; research into treatment options; and research into effective tests and biomarkers.

ILADS (the International Lyme and Associated Disease Society) has developed USA guidelines which do recognise the complexities of the disease and which are in the US National Guidelines Clearinghouse. German guidelines also exist which acknowledge issues with testing and the possibility of lack of response to treatment.

Late-Stage Borrelia Infection Involves Persistence

There is mounting evidence of bacterial persistence. As far back as 1993 Dr. Kenneth Liegner concluded that "individuals who have demonstrated relapses following aggressive treatment may require an open-ended antibiotic approach provided that they are deriving clinical benefit and not experiencing any adverse effects and that they wish to be treated."

Seronegative chronic relapsing neuroborreliosis has been known of since at least 1996.

In 2013, it was stated that "accumulating evidence indicates that Lyme disease spirochetes are adapted to persist in immune competent hosts, and that they are able to remain infective despite aggressive antibiotic challenge. … Credible evidence supports the conclusion that LD can be a recalcitrant and chronic relapsing infection in animal hosts".

In 2014, a mouse study confirmed the findings of previous studies there was "resurgence of spirochete DNA in multiple tissues at 12 months [after treatment], with levels nearly equivalent to those found in saline-treated mice".

In 2015, research at Northeastern University found that "Borrelia burgdorferi, the causative agent of Lyme Disease, forms drug-tolerant persister cells". Further research has concluded that there is “substantial evidence that Borrelia burgdorferi is capable of forming biofilm in vitro. Biofilm formation by Borrelia species might play an important role in their survival in diverse environmental conditions by providing refuge to individual cells.” In 2017, research at Johns Hopkins University found that even "ceftriaxone pulse dosing fails to eradicate biofilm-like microcolony B. burgdorferi persisters".

In a recent letter, it was stated that "There is 16S ribosomal RNA gene sequencing–based evidence of persistent infection by Borrelia burgdorferi and related spirochetes in patients after full courses of antibiotic treatment for Lyme disease. ... These cases proven by gene sequencing cannot be dismissed by the usual suspect of laboratory PCR contaminations."

Recent research found that "Borrelia burgdorferi manipulates innate and adaptive immunity to establish persistence in rodent reservoir hosts". Another paper reviews the mechanism of persistence via sleeper cells. Another study has found that extracellular, live spirochetes accumulate in lymph nodes and hypothesises that this tricks the immune system into making an inadequate response. Biofilm protecting bacteria has been found in human tissues. A very recent review states that "The presence of biofilm may explain the low rate of Borrelia detection in the blood of infected patients as well as the ability of the spirochetes to evade the host immune system and resist the antibiotic therapy".

In 2017, in a study in primates to comprehensively examine pathology associated with persistence of B. burgdorferi in the late stage of LD following antibiotic therapy, the findings "support the notion that chronic Lyme disease symptoms can be attributable to residual inflammation in and around tissues that harbor a low burden of persistent host-adapted spirochetes and/or residual antigen". No monkeys were cured with antibiotic treatment which matched or exceeded recommendations for the treatment of Lyme disease made by such authorities as the British Infection Association (BIA), and the National Institute of Clinical and Care Excellence (NICE).

In 2018, a pilot study in humans concluded that "Using multiple corroborative detection methods, we showed that patients with persistent Lyme disease symptoms may have ongoing spirochetal infection despite antibiotic treatment, similar to findings in non-human primates".

Another study demonstrates "that following Bb infection elevations and clonal expansion of blood plasmablasts are correlated with rapid return to health, while poor plasmablast responses are associated with a longer duration of symptoms following doxycycline treatment. ... Resolution of symptoms following antibiotic treatment was associated with robust plasmablast responses encoding Bb-static antibodies, suggesting that plasmablast-derived anti-Bb antibodies could provide the basis for next-generation antibody-based therapeutics for Lyme disease".

Another study has shown "that a spirochete surface protein ... orchestrates unique host immune evasion strategies crucial for early spirochete infection in mammals. It suppresses host complement-mediated killing and neutrophil-derived microbicidal responses, including induction of antimicrobial peptides, and promotes pathogen dissemination. ... These studies highlight the evolution of plasticity in immune evasion strategies of atypical pathogens like B. burgdorferi, which is remarkably adapted to persist in multiple hosts and on a long-term basis without host clearance".

The evidence for proof of chronic Lyme and its severity is discussed in a recent article. One report cites over 700 papers that support the evidence of persistence of Lyme and other tick-borne diseases. It is argued that a post-mortem study is required to end the disagreement in the medical community. The US Tick-borne Disease Working Group have issued a report where they acknowledge the many studies showing persistence and document the gaps in knowledge.

In a book review in Nature magazine, Dr. James Logan, Head of Department of Disease Control at the London School of Hygiene and Tropical Medicine, states "Clinicians are now beginning to acknowledge both the complexity of Lyme disease and patients’ needs. ... What’s particularly pressing is the need for a definitive test to detect the spirochaetes that cause this devastating disease."

Alternative Treatments are More Effective

Patient experience in Scotland is that, if treatment is offered, it normally involves giving doxycycline antibiotics, often for a period of up to one month in accordance with the IDSA guidelines. Serious cases are occasionally treated with 2-4 weeks of intravenous ceftriaxone. However, current treatment does not acknowledge persistence in long-term infection, for which much more effective treatment is emerging. Patients who have paid for private treatment abroad have recovered or obtained remission of infection through such treatments.

According to an article in Nature, "we identified 165 agents approved for use in other disease conditions that had more activity than doxycycline and amoxicillin against B. burgdorferi persisters. The top 27 drug candidates from the 165 hits were confirmed to have higher anti-persister activity than the current frontline antibiotics. Among the top 27 confirmed drug candidates from the 165 hits, daptomycin, clofazimine, carbomycin, sulfa drugs (e.g., sulfamethoxazole), and certain cephalosporins (e.g. cefoperazone) had the highest anti-persister activity. In addition, some drug candidates, such as daptomycin and clofazimine (which had the highest activity against non-growing persisters), had relatively poor activity or a high minimal inhibitory concentration (MIC) against growing B. burgdorferi. Our findings may have implications for the development of a more effective treatment for Lyme disease and for the relief of long-term symptoms that afflict some Lyme disease patients".

In a more recent study, it was found that "Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Microcolony B. burgdorferi Persisters Which Are Sterilized by Daptomycin/ Doxycycline/Cefuroxime without Pulse Dosing". Anecdotal evidence of recent clinical trials in the USA suggests treatment success is possible.

In an alternative study, “Dapsone is a novel and effective “persister” drug for those with PTLDS and associated tick-borne co-infections who have failed classical antibiotic protocols. Further prospective trials must determine the DDS dose, length of treatment and best combination antibiotic therapy in order to effect a long-term health benefit.” A related study concluded that dapsone combined therapy "decreased eight major Lyme symptoms severity and improved treatment outcomes among patients with chronic Lyme disease/PTLDS and associated coinfections".

In a recent commentary it has been stated "Twenty-five years ago, the AIDS epidemic was wreaking havoc around the world. Although 'HIV denialists' threatened to undermine research efforts to combat the epidemic, development of targeted antiviral therapy eventually provided effective treatment for the disease. Now the Lyme disease epidemic is wreaking havoc around the world, and 'Lyme denialists' are undermining efforts to combat the epidemic. Drawing on our experience with the AIDS epidemic, there is a significant need to develop targeted therapy to control the Lyme disease epidemic."

Alternative Treatments may Include Natural Products

Natural products have been found to be useful in treating borreliosis and stevia shows promise. “The effectiveness of Stevia was compared to doxycycline, cefoperazone, daptomycin, and their combinations. Our results demonstrated that Stevia had significant effect in eliminating B. burgdorferi spirochetes and persisters. ... When Stevia and the three antibiotics were tested against attached biofilms, Stevia significantly reduced B. burgdorferi forms. Results from this study suggest that a natural product such as Stevia leaf extract could be considered as an effective agent against B. burgdorferi”.

In another study, “we tested the efficacy of 15 phytochemicals and micronutrients against three morphological forms of Borrelia burgdoferi and Borrelia garinii: spirochetes, latent rounded forms and biofilm. … The most effective antimicrobial compounds against all morphological forms of the two tested Borrelia sp. were baicalein and monolaurin. This might indicate that the presence of fatty acid and phenyl groups is important for comprehensive antibacterial activity. This study reveals the potential of phytochemicals as an important tool in the fight against the species of Borrelia causing Lyme disease.”

In very recent research into the antimicrobial activity of essential oils, "the top 5 essential oils (oregano, cinnamon bark, clove bud, citronella, and wintergreen) at a low concentration of 0.25% showed more activity than the persister drug daptomycin (40 microM). An interesting observation is that the highly active essential oils were found to have excellent anti-biofilm ability as shown by their ability to dissolve the aggregated biofilm-like structures."

In a further study, garlic oil and cinnamon were found to be particularly active against borrelia.

Multiple Doses of Pulsed Treatment may be Required

In another study of persister cells, “we examined the ability of B. burgdorferi to form persisters. Killing of growing cultures of B. burgdorferi with antibiotics used to treat the disease was distinctly biphasic, with a small subpopulation of surviving cells. Upon regrowth, these cells formed a new subpopulation of antibiotic-tolerant cells, indicating that these are persisters rather than resistant mutants. The level of persisters increased sharply as the culture transitioned from exponential to stationary phase. Combinations of antibiotics did not improve killing. Daptomycin, a membrane-active bactericidal antibiotic, killed stationary phase cells, but not persisters. Mitomycin C, an anti-cancer agent that forms adducts with DNA, killed persisters and eradicated both growing and stationary cultures of B. burgdorferi. Finally, we examined the ability of pulse-dosing an antibiotic to eliminate persisters. After addition of ceftriaxone, the antibiotic was washed away, surviving persisters were allowed to resuscitate, and antibiotic was added again. Four pulse-doses of ceftriaxone killed persisters, eradicating all live bacteria in the culture.”

A review in 2013 concluded  that "future research on antibiotic treatment for LD in animal hosts should assess the effectiveness of pulsed, variable combinations of antibiotics for their abilities to disrupt the protective niches and evasive methods favored by these flexibly adaptive spirochetes. For example, use of a cephalosporin against spirochetal forms in the vascular compartment might be combined with pulsed dosing of tinidazole to cover spirochetal and atypical forms in matrix compartments. Such a regimen may yield better long-term outcomes than ceftriaxone or doxycycline alone."

Co-infections Make Treatment More Complex

Co-infection with other tick-borne pathogens is very common and has been found to increase the length and severity of illness. A survey run by Caudwell LymeCo is so far indicating that 94% of UK patients with Lyme disease believe they have at least one co-infection.  Examples of infections which can be transmitted by ticks at the same time as borrelia infection include bartonella, babesia, anaplasmosis, and erlichia.  Lyme Disease can also suppress the immune system and allow latent infections to come to the fore.  Examples include Epstein Barr and Herpes viruses. Many patients have positive serology in private tests for infections with bartonella, babesia, anaplasma, mycoplasma pneumoniae, and chlamydia pneumoniae, amonst others, and yet these results are ignored by clinicians who state that it would be unlucky to be multiply infected. Some co-infections are developing antibiotic resistance and "reducing the level of immunosuppression when possible would appear to be a desirable strategy".  A French study has shown the extent to which co-infections occur and concluded that multiple "co-infections are the rule rather than the exception".  A study in Nature has conlcuded that there is "an 85% probability that a randomly selected TBD patient will respond to Borrelia and other related TBD microbes rather than to Borrelia alone. A paradigm shift is required in current healthcare policies to diagnose TBD so that patients can get tested and treated even for opportunistic infections." 

In a recent UK paper, it was suggested that patients who are chronically ill but seronegative "have a different disease from Lyme disease and therefore an alternative name, chronic arthropod-borne neuropathy (CAN), and case definition for this condition is proposed". Borrelia valaisiana has been found to have a different mechanism of action and is not currently tested for, which might provide one explanation. Patients test positive for mycoplasma pneumoniae and chlaymdia pneumoniae which might provide another.

Many European patients are testing positive in private tests for babesia duncanii. Research has shown it is difficult to treat.

As stated recently, "Lyme disease is one of the most important controversy in medicine history. Despite its previous description in Europe at the end of the 19th century and at the beginning of the 20th century, it has been officially described in the USA in the early seventies. A small group of experts from the Infectious Diseases Society of America (IDSA) described the disease on expert opinion basis and not on scientific data. They declared and published that the disease was rare, easily diagnosed with very efficient serologic tests, easily cured with 2 or 3 weeks of antibiotic treatment, and that a chronic form of the disease did not exist.

However, the medical literature, including articles in major journals, is rich in publications showing that the causative agent, Borrelia burgdorferi, could be isolated by culture or PCR from seronegative patients and providing evidence that Borrelia sp. can persist in blood and tissues despite several weeks or months of antibiotic treatment. As emphasized by the ECDC in April 2016, Lyme serology is quite impossible to calibrate properly. The cause is the fact that, in absence of a diagnostic gold standard, it is impossible to define for sure populations of patients or controls. A meta-analysis published at the end of 2016 showed that the sensitivity of Lyme serology was less than 60%.

Moreover, serologic tests only exist for one strain of Borrelia in North America and 3 strains in Europe. There is no test available for the numerous Borrelia sp. found in ticks and already isolated from patients. We know from publications that patients suspected to have a chronic Lyme disease may harbor other bacteria such as Anaplasma, Bartonella (including strains previously unknown in humans), Ehrlichia, Neoerlichia, Rickettsia, Coxiella, Francisella, etc. They can also harbor parasites such as Babesia sp. Some labs, including veterinary labs, have developed promising PCR methods.

The consequence of the lack of reliable diagnostic tests in routine for Lyme and co-infections is the suffering and the wandering of millions of patients in the world, rejected by the medical community and often ending in psychiatry wards. Not a single controlled randomized study has evaluated the efficacy of prolonged anti-infectious treatment (longer than 3 months) on the chronic form of the disease. Despite the important underestimation of the incidence measured on serology, the official incidence of the disease is rising in many countries in America and Europe in huge proportions (such as 10 fold increase or more in a decade). Research funding is urgently needed to better manage this public health threatening infectious disease."

Cost

If the cost of treatment seems high, consider the cost of not treating. A recent study concluded that "If governments do not finance IV treatment with antibiotics for chronic Lyme disease, then the estimated government cost for chronic Lyme disease for 2018 for the USA is 10.1 billion USD and in Europe 20.1 billion EUR. If governments in the USA and Europe want to minimize future costs and maximize future revenues, then they should pay for IV antibiotic treatment up to a year even if the estimated cure rate is as low as 25%. The cost for governments of having chronic Lyme patients sick in perpetuity is very large".

Human Rights Issues

Doctors and others attempting to help Lyme disease patients have been harassed, making others unwilling to get involved. The human rights defenders of Lyme and relapsing fever borreliosis patients include members of non-governmental organizations, patient groups, government officials, elected officials, scientists, medical professionals, researchers and laboratory and clinic owners. They:

• have been consistently threatened with the loss of their professional licenses and livelihoods
• have had their livelihoods destroyed and licenses removed
• are routinely targeted for harassment, defamation, slander and libel
• are burdened with probationary measures that curtail their freedom of movement and assembly and their right to free speech and associational life
• experience false accusations, undue process and conviction

These documented violations have often targeted the human rights defenders themselves, as well as the organizations and mechanisms through which they work.